GB1569558A - 1-iodo (or chloro)-3-3-protected hydroxy-w-bicycloalkyl-1-alkenes - Google Patents

Description

PATENT SPECIFICATION

( 11) 1 569 558 ( 21) Application No 40081/78 ( 62) Divided Out of No 1568781 ( 31) Convention Application No.

( 22) Filed 26 Jan 1977 ( 19) 657221 ( 32) Filed 11 Feb 1976 in ( 33) United States of America (US) ( 44) Complete Specification Published 18 Jun 1980 ( 51) INT CL 3 C 07 C 43/18 C 07 D 309/12 C 07 F 7/08 ( 52) Index at Acceptance C 2 C 1174 1200 1206 121 X 200 204 222 225 226 227 22 Y 237 304 305 30 Y 313 314 315 316 31 Y 339 351 355 Y 360 361 362 364 366 367 368 36 Y 37 X 386 401 40 Y 43 X 440 442 446 449 490 49 X 500 505 507 509 Y 562 56 Y 623 625 628 633 634 638 652 655 658 659 65 X 665 668 73 Y 776 778 779 AA BM BW HG UN WN WZ ( 54)1-IODO (OR CHLORO)-3-PROTECTED HYDROXY-W BICYCLOALKYL-1-ALKENES ( 71) We, MILES LABORATORIES INC a Corporation organised and existing under the laws of the State of Indiana United States of America, of 1127 Myrtle Street, Elkhart, Indiana 46514, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us the method by which it is to be performed, to be particularly described in and by the following statement.

This invention relates to 1-iodo (or bromo)-3-protected hydroxy-wbicycloalkyl-1alkenes.

In our Application No 3183/77 (Serial No 1568781) we describe and claim bicycloalkyl analogues or derivatives of prostaglandine A, E and F which are useful modifiers of smooth muscle activity These compounds have valuable pharmacological properties as platelet anti-aggregating agents and gastric anti-secretory agents The compounds are also valuable pharmacological agents for increasing femoral blood flow and decreasing blood pressure and heart rate.

These bicycloalkyl analogues of prostaglandins having the following structural formula; 1 L Q"ot,/^ _" (CI ') -B DJ (III) In Formula III:

g is O or an integer from 1 to 10:

D is a R-hydroxymethylene or S-hydroxymethylene radical:

J is a methylene, R-hydroxymethylene or S-hydroxymethylene:

K is a methylene or ethylene with the proviso that K is ethylene only when J is methylene or J and K together form a vinylene radical:

L is a carbonyl, R-hydroxymethylene or S-hydroxymethylene radical:

Q is an ethylene or Z-vinylene radical:

T is an alkoxycarbonyl having from 1 to 3 carbon atoms in the alkyl radical, carboxyl, or hydroxymethyl radical and B is a bicycloalkyl radical of the formula:

ttn On ior tn PS 222 1 569 558 11 I H where m and p are integers from 1 to 4; N is O or an integer from 1 to 4 with the proviso that n is not 1 when m and p are both 2 and p is not 1 when m and N are both 2: and the sum of m, N and p is greater than or equal to 3 and where the point of attachment of the alkylene chain 10 (CH 2)m bridge or bridgehead position and pharmacologically acceptable non-toxic salts thereof when T is a carboxy radical.

The numbering system and the stereochemistry nomenclature used are according to the I.U P A C definitive and tentative rules which designate the carboxylic acid side chain as the parent compound In formula III, serpentive line (-) denotes a covalent bond which 15 can be either in the alpha configuration (projecting below the plane of a reference carbon atom) or in the beta configuration (projecting above the plane of a reference carbon atom).

As used herein, cis or trans isomerism around double bonds respectively is designated by affixes Z (zusammen) and E (entgegen) Chirality around asymmetric carbon atoms is designated by affixes R (rectus) and S (sinister) 20 Compounds having formula III can be prepared via the 1,4-conjugate addition of organocopper reagents to cyclopentenones as reported by Sih, et al, (J Amer Chem.

SOC, & 7/8: 857,865 ( 1975) and references cited therein) The novel compounds of formula

III are prepared according to the reaction sequence depicted in Reaction Scheme A.

Reaction scheme A 25 X 2-/(clfzg}-B (y) OA (l) lithium (metallic or lower alk)yl lithium) (V) ( 2) Copper(r) Complex(vi) 30 01 ( 3) -T' (V 11) 0 C"" ') ' 35 K 4 '('I TI c Pg vr) ( 4) Iak acid at 20 ' to 45 'C.

o J r V Cl) T 40 4 (Sd) Wchal: cid \ (Sb) Na B Il 14/alcohol.

a.nd1t 4 O 45 \ % J,, -v \D(c 12) g \ J//t D ( c" z)g'-" (l Ia) ( 1 ff) B 50 - /, o 2.

J (c 2) g-1 < ( 1 llb) (Sc) Ester hydrolysis.

Wherein J' is methylene or = C Ho A where A is a hydroxy protective group as defined 55 below; K' is methylene or ethylene provided that K' is ethylene only when J' is methylene, T' is (C 1-3 alkoxy) carbonyl or CH 2 OA: T" is (C 1-3 alkoxy) carbonyl or hydroxy methyl and J" is methylene R-hydroxy methylene or S-hydroxymethylene.

The intermediates of formula IV wherein:

X is an iodine or bromine atom: 60 A is an acid-labile protecting group selected from 1-ethoxyethyl trimethylsilyl, tert-butyl-dimethylsilyl, 1-ethoxy-1-methylethyl triphenyl-methyl and tetrahydroxpyran-2yl radical:

g is O or an integer from 1 to 10; and B is a bicycloalkyl radical of the formula: 65 3 1 569 558 3 II c c 5 H where m and p are integers having a value of from 1 to 4; N is O or an integer having a value of from 1 to 4 provided that the sum of m, N and p is greater than or equal to 3 and the point of attachment of the alkylene chain (CH 2), to the bicycloalkyl radical is in the (CH 2)m 10 bridge or in the bridgehead position are novel and form the subject of the present invention.

These compounds can be prepared according to the reaction sequence depicted in Reaction Scheme B Examples of compounds of formula IV include: 1-iodo-3-( 1ethoxyethoxy)-3-(bicyclol 3 2 O lhept-3-yl) 1 E-propene; 1-iodo-3(ethoxyethoxy)-7 15 (bicyclol 3 2 1 loct 2-yl)-IE-heptene: 2-iodo-3-)2-ethoxyethoxy)-7-) bicyclol 4 4 O l dec-2-yl(l E-heptene and 1-iodo-3 p( 1-ethoxyethoxy)-4-(bicyclol 2 2 1 lhept 2-yl)l E-butene The synthesis of compound IV from the corresponding carboxylic acid I Va can be accomplished via the reaction sequence of Reaction Scheme B by well-known organic chemistry prodedures 20 REACTION SCHIEMIE B o HO/' (CH 2)o -n' (Ird') 1) SOC 12 or Oxalyl chloride or 25 similar reagent.

CI (CH 2) (r Bb) 2) Al C 13 or other similar Lewis 30 Al 13 3 acid; Acetylene; CCI 4 or C 12 C 12 or similar inert solvent.

O O cl -(CH,)a-1 (lye) 35 3) Nal, Na Br or L i Br or other similar soluble bromide or iodide salt; Acetone.

-0 40 xtf- -(C Hz)a-9-8 (n'd) 4) Na BH 4 or Li AIH 4 or other similar reducing agent/solvent.

(C ('e) 45 01 l S) Hydroxyl protecting agent such that A is acid labile 50 X, /(CH,) P 1 (Iv) OA In I Va-I Vb the carboxylic acid I Va is converted to the acid chlorice I Vb using an acid chloride forming reagent such as thionyl chloride, oxalyl chloride or phosphorus trichloride 55 as described in Fieser & Fieser, Reagents for Organic Synthesis 1: 1158, J Wiley & Sons Inc ( 1967) In I Vb >I Vc the acid chloride I Vb is reacted with acetylene in an inert solvent, such as carbon tetrachloride or methylene chloride, in the presence of a Lewis acid such as aluminium chloride or stannic chloride to produce the l 3-chlorovinyl ketone Vc as described in Chem Rev, 161 ( 1965) and Org Synth, IV: 186, J Wiley & sons Inc ( 1963) In I Vc 60 >I Vd, the 13-chlorovinyl ketone I Vc is converted into the corresponding 13-iodo or P 3-bromo-vinyl ketone I Vd, where X is an iodine or bromine atom, using a soluble salt, such as sodium iodide, sodium bromide or lithium bromide, in a polar inert solvent, such as acetone or acetonitrile as described in J Amer Chem Soc, 94: 7210 ( 1972) In I Vd-I Ve, compound I Vd is reduced to the corresponding 13-iodo or l 3-bromo-vinyl alcohol using a 65 A " 1 569 558 4 suitable reducing agent, such as sodium borohyxdride in an alcohol or lithium aluminium hydride in an ether as described in J Amer Chem Soc, 94 7210 ( 1972) In I Ve >IV, compound I Ve is protected with a suitable hydroxyl-protecting agent (A) by reaction with, for example, dihydropyran or ethyl vinyl ether in the presence of an acid catalyst such as p-toluene-sulphonic acid, 98 % sulphuric acid or phosphorus oxychloride; or a trialkylsilyl 5 chloride, such as trimethylsilyl chloride or t-butyldimethylsilyl chloride, or triphenylmethyl bromide in the presence of a basic catalyst such as triethylamine or imidazole Any hydroxyl protecting group that is removable under midly acid conditions and is stable alkyllithium and alkylcopper (I) reagents can also be suitably used, see J Org Chem 37: 1947 ( 1972).

Examples of the corresponding carboxylic acids having formula I Va include: bicyc 10 lol 3 2 Olheptane-3-carboxylic acid; 5;(bicyclol 3 2 lloct-2-yl)pentanoic acid; 5(bicyclol 4 4 O ldec-2-yl)pentanoic acid; and (bicyclol 2 2 1 lhept-2-yl) acetic acid The bicycloalkyl carboxylic acids of formula I Va are either commercially available or can be prepared by well-known techniques from commercially available materials For example, the compound cis-1,2-cyclobutanedicarboxylic anhydride is reduced with a suitable reagent, 15 such as lithium aluminium hydride, lithium borohydride, lithium tri-tbutoxyaluminium hydride or borane, to produce= cis-1,2-bis(hydroxymethyl)cyclobutane This latter compound is then substituted for trans-12-bis-(hydroxymethyl)cyclobutane in the procedure described in J Org Chem, 29 2914 ( 2964) for the preparation of trans(bicyclol 3 2 O lhept3-yl)carboxylic acid The product of this procedure is thus cis-(bicyclo-l 3 2)lhept-3 20 yl)carboxylic acid This latter compound is used in the reaction sequence depicted in Reaction Scheme B to produce 1-iodo-3-( 1-ethoxyethoxy)-3-(bicyclol 3 2 O lhept-3-yl)-IEpropene.

Other commercially available cis or trans isomers of 1 2dicarboxycycloalkyl: 1 2bis(hydroxy-methyl)cycloalkyl: or 1 2-bis(bromomethyl)cycloalkyl may be used in the 25 above procedure to produce compounds of structure I Va where g is O and B is /Àl 30 These latter compounds lead to prostaglandins of structure III in which g is O m is 3, N is O and p is 1 to 4.

5-(Bicyclol 3 2 1 loct-2-yl)pentanoic acid can be prepared by the following procedure The compound 2-oxobicyclol 3 2 11 octane is reacted with a suitable base, such as sodium hydride, potassium hydride, lithium hydride, lithium diisopropylamide, or lithium 35 t-butoxide, and ( 4-carboxybutyl)triphenyl phosphonium bromide in an inert solvent such as dimethyl sulphoxide, benzene, diethyl ether t-butanol or mixtures thereof via a Wittig reaction (Tet Let, 4: 311 l 1970 l) to produce the intermediate compounds 5(bicyclol 3 2 1 l-oct-2-ylidene)pentanoic acid This latter compound is catalytically reduced in a suitable solvent such as ethanol or other alcohol or an organic acid in the presence of a 40 hydrogenation catalyst such as platinum oxide Pd on carbon Ru O,, or RaNi and a reducing agent such as hydrogen or diimide to produce 5-(bicyclo-l 3 21 loct-2-yl)pentanoic acid This latter compound is used in the reaction sequence depicted in Reaction Scheme B to produce 1-iodo-3-( 1-ethoxyethoxy)-7-(bicyclol 3 2 1 loct-2-yl)-1 Eheptene.

Other commercially available or easily prepared oxobicvclolm n plalkanes can be used in 45 place of 2-oxobicyclol 3 2 1 loctane in the Wittig reaction to yield a variety of 5(bicyclolm n plalkylidene)pentanoic acids which can then be used in the synthesis of a variety of prostaglandins with Structure III For example cis or trans (bicyclol 4 4 O ldecan1-one) may be used in the above Wittig reaction followed by the reduction to produce 1-iodo-3-( 1-ethoxyethoxy)-7-(bicyclol 4 4 0 ldec-1-yl)-l E-heptene 50 Easily prepared (co-carboxyalkyl)triphenyl-phosphonium bromide reagents may be used in place of( 4-carboxybutyl)triphenylphosphonium bromide in the Wittig reaction to yield o-(bicyclolm n p lalkylidene) alkanoic acids which can then be used in the synthesis of prostaglandins with structure III The (o-carboxy-alkyl) triphenylphosphonium bromide reagents are most easily prepared by reacting triphenylphosphine with an o-bromalkanoic 55 acid in an inert solvent such as benzene, acetonitrile or diethyl ether, usually at an elevated temperature such as solvent reflux The products are usually isolated as crystalline salts which separate from the reaction mixture upon cooling The following Examples further illustrate the present invention.

60 Example 1

This example illustrates a typical preparation of the compound 1-iodo-3 RS-( 1ethoxyethoxy)-7-(bicyclol 3 2 1 loct-2-yl)-1-E-heptene.

A Preparation of 5-(bicvclol 3 2 1 loct-2-vl-idente)pentanoic acid.

A mixture of 3 92 g ( 93 mmol) of sodium hydride ( 57 % oil dispersion) and 30 ml of dry 65 A 1 569 558 5 dimethyl sulphoxide was heated at 70-80 C under nitrogen until gas evolution ceased ( 2 5 hours) The mixture was cooled, and 19 7 g ( 44 3 mmol) of 4-(carboxybutyl) triphenylphosphonium bromide (Aldrich # 15,794-5)was added, followed by 20 ml of dimethyl sulphoxide The resulting deep red mixture was stirred for 45 minutes at room temperature under nitrogen before a solution of 5 0 g ( 50 2 mmol) of bicyclol 3 2 1 l-octan 5 2-one (Aldrich # 11,903-2) in 20 ml of dimethyl sulphoxide was added dropwise over 1 75 hours The resulting mixture was stirred for 16 hours at room temperature before it was quenched by the addition of 125 ml of water The resulting solution was extracted with three 250 ml portions of diethyl ether/ethyl acetate-1:1 (V/V) to remove neutral by-products The remaining aqueous phase was acidified by the addition of 15 ml of 10 concentrated hydrochloric acid and extracted with three 250 ml portions of diethyl ether-hexane-1:1 (V/V) These combined acidic ether-hexane extracts were dried (Mg SO 4), and evaporated in vacuo to yield 6 0 g of crude 5-(bicyclol 3 2 1 l-oct-1ylidene)pentanoic acid as an oil This oil was purified by chromatography on silica gel 60 (elution with CHC 13 containing 0 5 % formic acid) to yield 4 1 g ( 49 %) of pure material as a colourless oil 15 Analysis IR:)CHC 13 max 5 87 lt 3 41 lt and 2 86 to 4 17 lx (broad) 20 NMR(DC 13) 6 3 0 broad, 1 H 6 4 9 broad triplet, 1 H 25 B Preparation of 5-(bicvclol 3 2 1 loct-2-yl)-pentanoic acid.

A solution of 3 4 g ( 16 3 mmol) of 5-(bicyclo-l 3 2 1 loct-2-ylidene) pentanoic acid in 100 ml of absolute ethanol was hydrogenated at 50 psi over 300 mg of platinum oxide in a Parr apparatus After 1 5 hours hydrogen uptake became slow After 4 hours the system was flushed with nitrogen, and the catalvst was removed by filtration through diatomaceous 30 earth filter aid ("'Celite") lRegistered Trade Markl The filtrate was evaporated in vacuo to yield 3 25 g ( 96 % of quite pure 5-(bicyclol 3 2 1 loct-2-yl)pentanoic acid as a colourless oil.

Analysis IR: x CHC 13 5 85 t, 3 41 t and 2 86 to 4 17 u 35 max (broad) NMR(CD C 13): 6 11 6, broad singlet, 1 H.

C Preparation of 2-Chloro-7-(bicvclol 3 2 1 l-oct-2-vl(-1 E-hepten-3-one.

A solution of 7 2 g ( 32 mmol) of 5-(bicyclo-l 3 2 1 loct-2-yl)pentanoic acid in 20 ml of 40 thionyl chloride was left overnight at room temperature under nitrogen The excess thionyl chloride and by-products were removed by evaporation in vacuo The resulting acid chloride ( 7 8 g) was used in the following procedure A 65 ml portion of carbon tetrachloride in a flask fitted with a gas addition tube, dropping funnel, and mechanical stirrer was saturated at O with acetylene which had been passed through an activated 45 aluminium oxide trap followed by two concentrated sulphuric acid traps A 5 2 g ( 40 mmol) portion of anhydrous aluminium chloride was added as acetylene was continuously bubbled through the mixture The above acid chloride was added dropwise followed by a small amount of carbon tetrachloride rinse Acetylene was bubbled through the resulting mixture for an additional 4 hours The mixture was then quenched with a 50 ml of crushed ice and 75 50 ml of brine The layers which resulted were separated The aqueous layer was extracted with three 75 ml portions of diethvl ether The combined ethereal extracts were washed with 10 % aqueous HC 1 three times, saturated aqueous sodium bicarbonate three times, dried (Mg SO 4), and evaporated in vacuo to yield 8 8 g of residue which was chromatographed on silica gel (benzene elution) to give 3 2 g ( 37 %) of pure 1-chloro-7 55 (bicyclol 3 2 1 loct-2-yl)-1 E-hepten-3-one:

Analysis NMR(CDC 13): 6 2 5 broad t J= 6 5 Hz 2 H 6 6 48 doublet, J= 13 5 Hz, 1 H 6 7 28 doublet J= 13 5 Hz, 1 H 60 D Preparation of 1-iodo-7-(bicyclo/3 2 1 J-oct-2-yl)-l E-hepten-3-one.

A solution of 3 2 g ( 13 mmol) of 1-chloro-7-(bicyclol 3 2 1 loct-2-yl)-l E 4-hepten-3-one and 7 5 g ( 50 mmol) of sodium iodide in 25 ml of dry acetone(distilled from potassium carbonate) was refluxed for 18 hours under nitrogen The solvent was removed in vacuo,, 65 "o 1 569 558 6 and the residue was taken up in 50 ml of water and then extracted three times with 30 ml portions of diethyl ether The combined ethereal extracts were washed with aqueous sodium thiosulphate, dried (Mg SO 4) and evaporated in vacuo to yield 3 8 g ( 88 % of 1-iodo-7-(bicyclol 3 2 1 loct-2-yl)-l E-hepten-3 one.

5 Analysis NMR(CDC 13): 6 2 5, broad t, J = 6 7 Hz, 2 H 6 7 08, doublet, J= 15 Hz, 1 H 6 7 78, doublet, J= 15 Hz, 1 H.

10 E Preparation of 1-iodo-7-(bicyclol 3 2 11-oct 2 vl)-l E-hepten-3 RS-ol.

To a solution of 3 8 g ( 10 9 mmol) of 1-iodo-7-(bicyclol 3 2 1 loct-2-yl) -l E-hepten-3-one in 50 ml of absolute ethanol under argon at o was added a slurry of 1 6 g ( 44 mmol) of sodium borohydride in 50 ml of ethanol The resulting mixture was stirred for 1 hour, and the solvent was removed in vacuo The residue was taken up in 100 ml of water and 15 extracted with three 100 ml portions of diethyl ether the combined extracts were dried (Mg SO 4) and evaporated in vacuo to yield 4 0 g ( 100 %) of 1-iodo-7(bicyclol 3 2 2 loct-2yl)-1 l E-hepten-3 rs-ol; Analysis IR: CHC 13 10 65 p 3 43 l, 2 91 and 2 79 20 max NMR(CDC 13): 6 4 1, broad, 1 H 6 6 15 to 6 75, complex 2 H.

F Preparation of 1-iodo-3 RS-( 1-ethoxyethoxv)-7-(bicvclol 3 2 lloct-2-vl) -l E-heptene 25 To a solution of 4 0 g ( 11 mmol) of 1-iodo-7-(bicyclol 3/8 s/4 /slOCT /4-YL(-l/s E-hepten3-ol in 15 ml of ethyl vinyl ether was added two drops of phosphorous oxychloride After standing for 18 hours at room temperature the resulting solution was washed with saturated aqueous sodium bicarbonate The wash solution was back extracted twice with diethyl ether The combined ethereal extracts were washed once with saturated aqueous sodium 30 chloride, dried (Mg SO 4) and evaporated to yield a yellow oil This yellow oil was chromatographed on silica gel (benzene elution) to yield 1 6 g of 1-uiodo3 RS-( 1ethoxyethoxy)-7-)bicyclo-l 3 2 1 loct-2-yl)-l E-heptene and 1 0 g of the unprotected starting material which was recycled The spectrum of pure product was:

Analysis NMR(CDC 13): 63 24 to 3 73, multiplet 2 H 35 6 3 97, broad, 1 H 6 4 67, quartet J= 5 3 Hz 1 H 6 6 08 to 6 65 multiplets 2 H.

Example 2 40

This example illustrates a typical preparation of 1-iodo-3 RS-( 1ethoxyethoxy)-7(bicyclol 4 4 10 ldec-2-yl)-l E-heptene.

A Preparation of 5-(bicyclol 4 4 O ldec-2-vlidene)pentanoic acid.

Repeating in a similar manner the procedure of Example 1 above but replacing bicyclol 4 4 O ldec-2-ylidene)pentanoic acid 45 Repeating in a similar manner the procedure of Example 1 above replacing bicyclol 3 2 1 loctan-2-one with bicyclol 4 4 O decan-2-one ( 2-decalone Aldrich # 15 506-3) yields the intermediate 5-(bicyclol 4 4 0 -dec-2-ylidene)pentanoic acid.

Analysis NMR(CDC 13): 6 5 0 triplet, J= 6 5 Hz 1 H 6 10 4 broad singlet 1 H 50 B Preparation of 5-(bicyclol 4 4 O ldec-2-vl)-pentanoic acid.

Repeating in a similar manner the procedure of Example l B above but replacing 5-(bicyclol 3 2 1 loct-2-ylidene)pentanoic acid with 5-bicyclol 4 4 O ldec-2-ylidene)pentanoic acid yields the intermediate 5-(bicyclol 4 4 O ldec-2-yl)pentanoic acid 55 Analysis NMR(CDC 13: 6 10 0 broad singlet 1 H C Preparation of 1-chloro-7-(bicvclo/4 4 O l-dec-2-yl)-i E-hepten-3-one.

Repeating in a similar manner the procedure of Example 1 C above, but replacing 5-(bicyclol 3 2 1 l-oct-2-yl)pentanoic acid with 5-(bicyclol 4 4 O ldec-2yl)-pentanoic acid yields the intermediate 1-chlor-7-(bicyclol 4 4 O ldec-2-yl)-l E-hepten-3one 60 Analysis NMR(CDC 13): 6 2 5 broad triplet J= 6 5 Hz 2 H 6 6 4, doublet, J= 13 Hz, 1 H 6 7 3, doublet J= 13 Hz 1 H.

D Preparation of l-iodo-7-(bicvclo/4 4 O l-dec-2-yl)-IE-hepten-3-one 65 f.

r 1 569 558 / Repeating in a similar manner the procedure of Example y above, but replacing 1-chloro-7-l 3 2 1 l-oct-2-yl)-1 E-epten-3-one with 1-chloro-7-(bicyclo-l 4 4 O ldec-2-yl)-1 Ehepten-3-one yields the intermediate 1-iodo-7-(bicyclol 4 4 O ldec-2-yl)l E-hepten-3-one.

Analysis NMR(CDC 13): 5 2 5, broad triplet, J= 6 5 Hz, 2 H 6 7 1, doublet, J= 14 Hz, 1 H 5 6 7 8, doublet, J= 14 Hz, 1 H E Preparation of 1-iodo-7-(bicyclo(bicyclol 4 4 Oldec-2-yl)-1 E-hepten-3 RS-ol.

Repeating in a similar manner the procedure of Example 1 E above, but replacing 1-iodo-7-(bicyclo-l 3 2 1 loct-2-yl)-l E-hepten-3-one with 1-iodo-7(bicyclo-l 4 4 O ldec-2-yl)le-hepten-3-one yields the intermediate 1-iodo-7-(bicyclol 4 4 O ldec-2yl)l E-hepten-3 RS 10 ol.

Analysis NMR(CDC 13): 6 4 17, multiplet, 1 H 6 6 0 to 7 0 multiplet, 2 H.

F Preparation of 1 -iodo-3 RS-( 1-ethoxy-ethoxy) -7-(bicyclol 4 4 Odec-2yl) -1 E-heptene.

Repeating in a similar manner the procedure of Example i F above, but replacing 15 1-iodo-7-(bicyclo-l 3 2 lloct-2-yl)-l E-hepten-3 RS-ol with 1-iodo-7 (bicyclol 4 4 O ldec-3-yl)1 E-hepten-3 RS-ol yields the intermediate 1-iodo-3 RS-( 1-ethoxyethoxy)7(bicyclol 4 4 O ldec-2-yl) l E-heptene.

Analysis NMR(CDC 13): 6 3 5 to 4 2, multiplet, 3 H 6 4 8, multiplet, 1 H 20 6 6 0 to 7 0 multiplet, 2 H.

Example 3

This example illustrates a typical preparation of 1-iodo-3 RS-( 1ethoxyethoxy)-3(bicyclol 3 2 O l-hept-3-yl)-l E-propene 25 A Preparation of cis-1,2-bis-(hvdroxymethyl)cvclobultane.

A solution of 50 0 g ( 0 40 mmol) of cis-1,2-cyclobutanedicarboxylic anhydride (Aldrich # 14,543-2) in 50 ml of diethyl ether and 75 ml of THF was added in small portions to a O C slurry of 21 0 g of lithium aluminium hydride in 200 ml of diethyl ether in a 500 ml three-necked roundbottomed flask equipped with a reflux condenser, mechanical stirrer, 30 addition funnel and argon inlet The reaction mixture was warmed to 50 C and stirred for 1 hour Ethyl acetate ( 31 0 ml) was added dropwise followed by 21 0 ml water, 21 0 ml 15 % w/v aqueous sodium hydroxide and 40 ml of water The reaction mixture was stirred for 18 hours at 25 C then filtered The filtrate was washed with brine and vacuum distilled to afford 21 5 g of cis-1,2-bis-(hydroxymethyl)cyclobutane as a clear oil, b p 94-97 (vacuum 35 pump).

Analysis IR:)CHC 13 2 78 lt, 3 0 It (broad), 5 9 t.

max NMR(CDC 13): 6 10-2 30, multiplet, 4 H, CH 2-CH 2 40 6 2 65 multiplet, 2 H CH-CH 6 3 60 multiplet, 4 H CH 2 OH 6 4 65 broad t 2 H, OH B Preparation of cis-1,2-bix(bronmomnethvl)-cvclobutane.

To 44 g of phosphorous tribromide (-10 C was added dropwise 10 7 g of distilled 45 cis-1 2-bis-(hydroxymethyl)cyclobutane over a 1 hour period The reacti) on mixture was warmed to 25 C and stirred for 2 hours, then heated to 80-85 C for 18 hours The reaction mixture was cooled in ice and cold water added The layers were separated and the aqueous layer was extracted with methylene chloride The organic extracts were combined, washed with 5 % w/v aqueous sodium carbonate and water, then distilled to yield 13 8 g of 50 cis-12,2-bis(bromomethyl)cyclobutane as a purple oil, b p 86 C (vacuum pump).

Analysis IR: CHC 13 3 4 u 7 O u, 8 1 p (no OH signal max observed NMR(CDC 13): 6 1 3 -2 5 multiplet, 4 HCH 2-CH 2 55 6 2 8 multiplet, 2 H CH-CH 6 3 5, multiplet, 2 H CH,-Br.

C Preparation of 3, 3-bix(ethoxycarbonvl)-bicyclol 3 2 O lheptane.

In a 250 ml (round bottomed flask equipped with mechanical stirring reflux condenser, addition funnel and argon inlet was placed 20 2 g of cis-12-bis(bromomethyl)cyclobutane, 60 12.4 ml diethyl malonate and 72 ml of dry-t-butanol The reaction mixture was refluxed and a solution of 19 9 g of potassium t-butoxide in 123 ml of t-butanol was added over 6 0 hour The reaction mixture was refluxed for 15 hours The reaction mixture was cooled by external application of an ice-water bath and an equal volume of water added The mixture was extracted with diethyl ether The ethereal extracts were washed with 3 N hydrochloric 65 1 569 558 acid abd 5 % w/v aqueous sodium bicarbonate, then dried (Mg SO 4), filtered and distilled in vacuo to yield 10 3 g of 3,3-bis-(ethoxycarbonul)bicyclol 3 2 10 lheptane as a clear oil b p.

100-105 C (vacuum pump).

Analysis IR: k CHC 113 5 85 t 5 max NMR(CDC 13) 6 1 22, pair of t, J= 7 O Hz broad, CH 2 CH 3 D 6 4 37 quartet, 4 H, CH 2 CH 3.

D Preparation of bicyclol 3 2 O lheptane-3,3-dicarboxvlic acid 10 A solution of 10 3 g of 3,3-bis(ethoxycarbonyl)-bicyclol 3 2 O lheptane in 68 ml of 16 % w/v potassium hydroxide in 1:1 v/v methanol-water was refluxed for 16 hours under argon The solvents were removed in vacuo and the residue dissolved in a minimum amount of water.

The solution was acidified with concentrated hydrochloric acid and the precipitated acid isolated by vacuum filtration to yield 6 9 g of bicyclol 3 2 O lheptane-3, 3-dicarboxylic acid as 15 a white solid, m p 161-170 .

Analysis NMR(DMSO-d 6): 6 7 65, broad singlet, 2 H, CO 2 H.

E.Preparation of cis-(bicyclol 3 2 Olhept-3-vl)-carboxylic acid.

Bicyclol 3 2 O lheptane-3,3-dicarboxylic acid ( 6 90 g) was heated at 190 C under argon for 1 hour to afford 4 75 g of cis-(bicyclol 3 2 O lhept-3-yl)-carboxylic acid as a brown oily solid 20 Analysis NMR(CDC 13): 6 10 18, broad singlet.

1 H, CO 2 H IR(CHC 13: 2 75-4 4 R (broad), 5 85 , 6 40 l.

F preparation of 1-chloro-3-(bicyclol 3 2 O l-hept-3-vl)-l E-propen-3-one.

Repeating in a similar manner the procedure of Example 1 C above, but replacing 25 5-(bicyclol 3 2 1 loct-2-yl)pentanoic acid with bicyclol 3 2 O lheptane-3carboxylic acid yields the intermediate 1-chloro-3-(bicyclol 3 2 0 lhept-3-yl)-l E-propen-3-one.

Analysis NMR(CDC 13): b 6 66 doublet J= 14 Hz 1 H 6 7 36 doublet, J= 14 Hz 1 H G Preparation of 1-iodo-3-(bicyclol 3 2 o I-hept-3-yl)-l E-propen-3-one 30 Repeating in a similar manner the procedure of Example 1 D above, but replacing 1-chloro-7-(bicyclo-l 3 2 1 loct-2-yl)-l E-hepten-3-one with 1-chloro-3(bicyclo-l 3 2 O lhept-3yl-l E-propen-3-one to yield the intermediate 1-iodo-3-(bicyclol 3 2 O lhept-3-yl)-i E-propen3-one.

Analysis NMR(CDC 13): 6 7 27 doublet J= 15 Hz 1 H 35 6 7 99, doublet, J= 15 Hz 1 H H Preparation of 1-iodo-3 (bicyclol 3 2 01-hept-3-yl)-6-propen-3 RS-ol.

Repeating in a similar manner the procedure of Example 1 E above, but replacing 1-iodo-7-(bicyclol 3 2 1 l-oct-2-yl)-l E-hepten-3-one with 1-iodo-3(bicyclo-l 3 2 O lhept-3-yl)1 E-propen-3-one yields the intermediate 1-iodo-3-(bicyclol 3 2 O lhept-3yl)-l E-propen 40 3 RS-ol.

Analysis NMR(CDC 13): 6 4 2, multiplet 1 H 6 6 26, doublet J= 15 Hz 1 H 6 6 62 doublet of doublets, Jx 15 and 6 Hz 1 H 45 I Preparation of 1 -iodo-3 RS-( 1-ethoxyethoxy) -3-(bicvclol 3 2 Ohept-3yl)-l E-propene.

Repeating in a similar manner the procedure of Example 1 F above, but replacing 1-iodo-7-(bicyclo-l 3 2 1 loct-3-yl)-l E-hepten-3 RS-ol with 1-iodo-3(bicyclo-l 3 2 O lhept-3yl)-l E-propen-3 RS-ol yields the intermediate 1-iodo-3 RS-( 1ethoxyethoxy)-3-(bicyclol 3 2 O lhept-3-yl)-l E-propen 50 Analysis 6 3 5 to 4 2, multiplet, 3 H 6 4 8, multiplet, 1 H 6 6 0 to 7 0, multiplet, 2 H.

Example 4 55

This Example illustrates a typical preparation of 1-iodo-3 RS-( 1ethoxyethoxy)-4(bicyclol 2 2 1 lhept-2-yl)-l E-butene.

A Preparation of 1-chloro-4-(bicvclo-/2 2 1 lhept-2-vl)-JE-buten-3-one.

Repeating in a similar manner the procedure of Example 1 C above, but replacing 5-(bicyclo-l 3 2 1 loct-2-yl)pentanoic acid with (bicyclol 2 2 1 l-hept-2yl)acetic acid (Aldrich 60 # 12,726-4) yields the intermediate 1-chloro-4-(bicyclol 3 2 1 lhept-2-yl) -l Ebuten-3-one.

Repeating in a similar manner the procedure of Example 1 D above, but replacing 1-chloro-7-(bicyclol 3 2 1 loct-2-yl)-hept-2-yl)-1 l E-propen-3-one with 1-chloro-4-(bicvclol 2 2 1 lhept-2-yl)-l Ebuten-3-one yields the intermediate 1-iodo4(bicyclol 2 2 1 lhept-2-yl)-l E-buten-3-one 65 1 569 558 Analysis NMR(CDC 13): 6 7 20, doublet, J= 15 Hz, 1 H 1 6 7 85, doublet, J= 15 Hz, 1 H, C Preparation of 1-iodo-4-(bicvclol 2 2 1 l-hept-2-vl) -1 E-buten-3 RS-ol.

Repeating in a similar manner the procedure of Example 1 E above, but replacing 1-iodo-7-(bicyclo-l 3 2 1 loct-2-yl-l E-hepten-3-one with 1-iodo-4(bicyclo-l 2,2, lhept-2-yl) 5 1 E-propen-3-one yields the intermediate 1-iodo-4-(bicyclol 2 2 llhept-2yl) 11 E-propen3 RS-ol.

Analysis NMR(CDC 13): 6 5 04, multiplet, 1 H 6 6 1 to 6 8, multiplet, 2 H.

D Preparation of 1-iodo-3 RS-( 1-ethoxv-ethoxy)-4-(bicyclol 2 2 1 lhept-2yl)-l Ebutene 10 Repeating in a similar manner the procedure of Example i F above, but replacing 1-iodo-7-(bicyclol 3 2 1 l-oct-2-yl)-l E-hepten-3 RS-ol with 1-iodo-4(bicyclol 2 2 1 l-hept-2yl)-l E-propen-3 RS-ol yields the intermediate 1-iodo-3 RS-( 1aethoxyethoxy)-4(bicyclol 2 2 1 lhept-2-yl)-l E-butene.

Analysis NMR(CDC 13): 6 3 5, multiplet, 3 H 15 6 4 7, multiplet, 1 H 6 6 1 to 6 6 multiplet, 2 H.

Claims (1)

1. WHAT WE CLAIM IS:

   1 A compound having the formula:

   20 X (CH 2)g-B OA wherein: 25 X is an iodine or bromine atom:

   A is an acid-labile protecting group which is 1-ethoxyethyl, trimethylsilyl, tert-butyldimethyl-silyl, 1-ethoxy-1-methylethyl tetrahydropyran-2-yl or triphenylmethyl radical:

   g is O or an integer from 1 to 10, and B is a bicycloalkyl radical of the formula: 30 IT C ( C T 2) (Ctl N ( 2)p c 35 It where m and p are independently integers from 1 to 4: N is O or an integer from 1 to 4 such that the sum of m, N and p is greater than or equal to 3 and the point of attachment of the alkylene chain (CH 2)g to the bicyclo-alkyl radical is in the (CH,)m bridge or in the 40 bridgehead position.

   2 A compound according to claim 1, wherein m has a value of 3 or 4 and N has a value of 0 or 1.

   3 A compound according to claim 1 wherein g has a value of from 0 to 4; m has a value of 3 or 4 N has a value of or 1; andvalueoforand as a value of from 2 to 4 45 4 1-Iodo-3 RS-( 1-ethoxyethoxy)-7-(bicyclo-l 3 2 1 oct-2-yl)-l E-heptene.

   1-Iodo-3 RS-( 1-ethoxvethoxy)-7-(bicyclo 4 4 0 dec-2-vll-l E-heptene.

   6 1-Iodo-3-RS-( 1-ethoxyethoxv)-3-(bicyclo-l 3 2 lhept-3-yl)-1 E-propene.

   7 1-Iodo-3 RS-( 1-ethoxyethoxy)-4-(bicyclol 2 2 1 lhept-2-yl)-1 E-butene.

   50 J.A KEMP & Co, Chartered Patent Agents, 14, South Square.

   Grav's Inn.

   LONDON WC 1 R 5 EU 55 Printed for Her Majest's Stationery Office, by Croydon Printing Company Limited Croydon, Surrey, 1980.

   Published b 5 The Patent Office 25 Southampton Buildings London WC 2 A l AY,from "hich copies may be obtained.

   f